Abstract
Background. This study was performed to investigate the influence of a short-term treatment with pioglitazone versus placebo on inflammatory activation of mononuclear cells (mRNA expression/protein secretion of inflammatory markers). Methods and Results. Sixty-three patients with well-controlled type 2 diabetes (52 males, 11 females, age (Mean ± SD): 66 ± 7 yrs, disease duration: 6.6 ± 9.6 yrs, HbA1c: 6.7 ± 0.6%) were randomized to additional 45 mg of pioglitazone or placebo to their existing metformin and sulfonylurea therpay for four weeks in a double-blind study design. Protein risk marker levels (hsCRP, MMP-9, MCP-1, etc.) and the expression of NFκB subunits and NFκB-modulated cytokines from isolated peripheral monocyte/macrophages were determined at baseline and endpoint. There were no changes in HbA1c, but significant biomarker improvements were seen with pioglitazone only. The mRNA marker expression was downregulated by pioglitazone and further up-regulated with placebo (e.g., P105 pioglitazone: −19%/placebo: +6%, RelA: −20%/+2%, MMP−9: −36%/+9%, TNFα: −10%/+14%, P < 0.05 between groups in all cases). Conclusions. Pioglitazone very rapidly down-regulated the activated state of peripheral monocytes/macrophages as assessed by mRNA expression of NFκB and NFκB-modulated cytokines and decreased plasma levels of cardiovascular risk marker proteins independent of glycemic control.
Highlights
Obesity has been demonstrated to be associated with metabolic syndrome and cardiovascular disease, including severe complications, like acute coronary syndrome, myocardial infarction, and stroke [1, 2]
It has been demonstrated by Ghanim and Coworkers that circulating mononuclear cells in obese patients are in PPAR Research a proinflammatory state with an increase in intranuclear NF-κB binding, a decrease in IκB-ß, and an increase in the transcription of proinflammatory genes regulated by NF-κB, including migration inhibitory factor (MIF), IL-6, tumor necrosis factor-α (TNFα), and matrix metalloproteinase 9 (MMP-9) [12]
We investigated the mRNA expression of the inhibitors to NF-κB (IκB-α and IκB-β) [26], p105, and Rel-A (p65 subunit) as measures for the quantity of intranuclear NF-κB [27], and several proinflammatory mediators and markers that are known to be modulated by NF-κB, such as TNFα, IL-6, MIF, and MMP-9 [5, 12, 28] before and after four weeks of treatment
Summary
Obesity has been demonstrated to be associated with metabolic syndrome and cardiovascular disease, including severe complications, like acute coronary syndrome, myocardial infarction, and stroke [1, 2]. It is believed that the crosstalk between the preadipocytes and other tissues contributes to a general up-regulation of the immune system, including an activation of circulating monocytes and macrophages, resulting in an increased risk for atherosclerosis and vascular disease [10, 11] It has been demonstrated by Ghanim and Coworkers that circulating mononuclear cells in obese patients are in PPAR Research a proinflammatory state with an increase in intranuclear NF-κB binding, a decrease in IκB-ß, and an increase in the transcription of proinflammatory genes regulated by NF-κB, including migration inhibitory factor (MIF), IL-6, TNFα, and matrix metalloproteinase 9 (MMP-9) [12]. Pioglitazone very rapidly down-regulated the activated state of peripheral monocytes/macrophages as assessed by mRNA expression of NFκB and NFκB-modulated cytokines and decreased plasma levels of cardiovascular risk marker proteins independent of glycemic control
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